U.S. patent number 4,011,312 [Application Number 05/590,358] was granted by the patent office on 1977-03-08 for prolonged release drug form for the treatment of bovine mastitis.
This patent grant is currently assigned to American Home Products Corporation. Invention is credited to Gerald L. Reuter, Andrew G. Tsuk.
United States Patent |
4,011,312 |
Reuter , et al. |
March 8, 1977 |
Prolonged release drug form for the treatment of bovine
mastitis
Abstract
A prolonged release drug dosage form for the treatment of bovine
mastitis, specifically suited for dry cow treatment, consists of an
antimicrobial agent dispersed in a matrix of a low molecular weight
polyester of glycolic and lactic acids, and shaped as a cylindrical
bougie for facile insertion into the teat canal. Said polyester
erodes by hydrolysis in the bioenvironment, providing a continuous
release of the medication throughout the desired duration of the
treatment. The low molecular weight polyesters have a glycolic acid
content of about 60 to 80 mole percent, a lactic acid content of
about 20 to 40 mole percent, and a molecular weight less than
2000.
Inventors: |
Reuter; Gerald L. (Plattsburgh,
NY), Tsuk; Andrew G. (Plattsburgh, NY) |
Assignee: |
American Home Products
Corporation (New York, NY)
|
Family
ID: |
24361923 |
Appl.
No.: |
05/590,358 |
Filed: |
June 25, 1975 |
Current U.S.
Class: |
514/152; 424/116;
424/115 |
Current CPC
Class: |
A61K
9/0041 (20130101); A61K 9/204 (20130101); C08G
63/08 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 9/20 (20060101); C08G
63/08 (20060101); C08G 63/00 (20060101); A61K
031/765 (); A61K 035/66 () |
Field of
Search: |
;424/227,78 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Rosen; Sam
Attorney, Agent or Firm: Venetianer; Stephen
Claims
We claim:
1. A bioerodable solid dosage form for the treatment of mastitis
comprising from about 30 to 70% by weight of a dosage form of at
least one antimicrobial agent intimately dispersed in a polyester
of glycolic and lactic acid, prepared by heating the polyester to a
temperature of about 60.degree.-80.degree. C, dispersing therein
the antimicrobial agent and thereafter rapidly cooling the
admixture, the polyester having a molecular weight less than 2,000,
a glycolic acid content of about 60 to 80 mole percent, and a
lactic acid content of about 20 to 40 mole percent.
2. The dosage form of claim 1 wherein the antimicrobial agent is
chlortetracycline.
3. A dosage form for the treatment of mastitis comprising a
suspension in a vegetable oil of about 30 to 50% by weight of the
subdivided dosage form of claim 1.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
Bovine mastitis is a serious problem, common in both lactating
dairy-type and beef-type animals. The management of this disease is
practiced mostly on the dairy-type animal where daily udder
handling and treatment is readily accomplished. Mechanical milking
machines may have caused an increased incidence of mastitis; the
true origins of the disease remain unknown. Bacterial organisms
identified from affected glands are varied; however, the species of
streptococcus and staphlococcus are most commonly isolated.
Good animal husbandry practice offers a lower general indidence of
mastitis. Antibiotics and chemotherapeutic agents have also
demonstrated advantage in restoring affected animals back to
healthy milk production. Vaccination has been shown to be useful in
minimizing mastitic attack in dairy goats; however, it has not been
demonstrated to be useful in cattle.
The control of mastitis in milk-producing animals is, therefore,
relegated to good management, selected animals, and medicinal
agents. The medications are used both for acute mastitic outbreaks
and as prophylactic remedies as dry cow preparations. Of special
significance are dosage forms which release the medication in a
sustained manner over several days, enabling the complete
eradication of the causative organism and guarding against
reinfection from the contaminated environment.
A major use for such dosage forms is in dry cow treatments, that is
during the approximate 4-week to 10-week period of time immediately
preceding the delivery of a calf. The delivery time is also known
as the time of freshening, suggesting the new lactation cycle. A
treatment approach during the dry period, nonlactating time,
reduces the potential of contamination of the milk supply by
medicinal agents and provides what should be an effective time
exposure of the medication in the udder tissue.
2. Description of Prior Art
Present products available are formulations of medicaments in
aqueous, glycol, or vegetable oil-type vehicles. For more prolonged
release of medicaments in the udder, mineral oil and vegetable oil
with gellants such as amorphous silicon dioxide, aluminum
stearates, and emulsifier-type agents are used. The capability for
varying the composition of the presently employed ingredients to
provide for long term release of medication is limited. The release
of the medication relies on its physical liberation from the
nonwater soluble and nonerodible vehicle and, thus, is not subject
to accurate control in the udder.
A further drawback of present mastitis treatment formulations is
that they may harbor pathogenic organisms. Some formulations are
sterile to obviate this hazard, others may be pasteurized, and
still others may pay no regard to this problem. Enteric pathogenic
organisms have been isolated from mineral oil, peanut oil, and
other pharmaceutic oils. To minimize problems of this type,
preservatives, e.g., chlorobutanol, have been employed.
A further drawback of present formulations, which are based on
nonerodible vehicles such as mineral oil, is that these vehicles
may persist in the udder or find their way into the milk
supply.
DESCRIPTION OF THE INVENTION
It has now been found that an antimicrobial agent incorporated in a
bioerodible matrix made from a polyester of glycolic and lactic
acid is an effective prolonged release dosage form for the
treatment of mastitis, especially for dry cow treatment. The
release of the drug is accomplished by the erosion of the matrix
which is readily controlled by manipulation of the copolymer
composition, the molecular weight of the polymer, and the amount of
drug incorporated in the matrix. The low molecular weight
polyesters melt at moderate temperatures to moderately viscous
fluids, in which the drug is readily dispersible. Surprisingly, the
above mentioned polyesters were found to be self-sterilizing and
apparently do not support the growth of tested strains of
pathogens. Yet, the polyester material was found nonirritating in
the cow's udder. The polyesters erode by hydrolysis to glycolic
and/or lactic acids, thus leaving no objectionable residues in the
udder or milk.
The polyesters useful in the solid dosage forms of the invention
are those having a molecular weight below 2000, a glycolic acid
content of about 60 to 80 mole percent, and a lactic acid content
of about 20 to 40 percent as described in U.S. Pat. No. 2,362,511
issued Nov. 14, 1944 to Teeters, the disclosure of which is
incorporated herein by reference.
The antimicrobial content of the solid dosage form can range from
about 30 to 70% by weight of the dosage form. The dosage forms are
prepared by simply heating the polyester to a temperature of about
60.degree.-80.degree. C., dispersing therein the antimicrobial
agent and thereafter rapidly cooling the admixture.
Advantageously the dosage forms are elongated and are prepared, for
example, by drawing the molten mix into a polyethylene tube and
allowing the mix to cool and solidify. Such a dosage form is in the
shape of a bougie having a crayonlike shape about 5 centimeters in
length and a diameter less than 0.5 centimeter. The bougie is
inserted into the teat canal through the teat sphincter where it
releases effective amounts of antimicrobial agent continuously for
several weeks.
Antimicrobial agents which can be employed are those effective
against species of streptococcus and/or staphlococcus and include
broad spectrum antibiotics, such as chlortetracycline,
oxytetracycline and tetracycline, and other antibiotics, either
singly or in combination, such as: streptomycin,
dihydrostreptomycin, the bacitracins, neomycin, polymixin-B,
chloramphenicol, erythromycin, amphotericin-B, colistin,
ampicillins, the penicillins, the cephalosporins, the cloxacillins,
lincomycin, nalidixic acid, novobiocin, kanamycin, ketasomycin,
oleandomycin, framycetin, nitrofurazone, furazolidone, furaltadone,
sulfonamides, complexed halogens, and other drugs specifically
useful in the treatment of bovine mastitis and generally useful in
topical medicinal applications.
DETAILED DESCRIPTION OF THE INVENTION
The preparation of the polyesters useful in this invention is
described in the following examples.
EXAMPLE I
Pure crystalline glycolic acid, 351 grams, USP lactic acid (85%),
131 milliliters, and 774 milliliters of distilled water were
introduced into a 1 liter resin kettle equipped with a nitrogen
inlet bubbling tube, thermometer, heating mantle, condenser and
receiver. Under a slow stream of nitrogen, water was distilled off
under atmospheric pressure until the pot temperature reached about
180.degree. C and the distillation was then continued under
aspirator vacuum with nitrogen bubbling through at a reduced rate
to provide stirring and to avoid bumping until the pot temperature
reached 219.degree. C, a total distillation time of about 12 hours.
The resin kettle was opened and its hot contents were poured into a
beaker, where it soon solidified. It is soluble in most commmon
solvents.
Determination of molecular weight: an amount of the product was
dissolved in hot dimethylsulfoxide, and the free carboxyl groups
were assayed by non-aqueous acidimetry. The acid number obtained
was 0.543 miliequivalents carboxyl per gram of product,
corresponding to a number average molecular weight of about
1800.
This lactic acid modified polyglycolide containing 75 mole %
glycolic acid, with a molecular wight of 1800, was used to make the
dosage forms of this invention by mixing one part by weight of
crystalline chlortetracycline hydrochloride with two parts by
weight of the molten polyester in a Brabender Mixer then drawing
the fluid mix into a polyethylene tube by vacuum and allowing the
mix to cool and solidify. The polyethylene tube can be refrigerated
and cut into bougie size lengths of about 5 centimeters and the
elongated dosage form withdrawn and used as desired.
Dissolution tests in vitro have shown that the drug is released
from the matrix continuously at adequate rates. Also, tests in
cows' udders have demonstrated that the polyester material in
bougie form offers no indications of udder irritation. Irritation
was adjudged by somatic cell counting and the California Mastitis
Test methods. Both of these techniques are known to people versed
in dairy management. The somatic cell count technique is described
by Schonberg in Milchkunde And Milchhygiene (1956) and the
California Mastitis Test is described in Journal of American
Veterinary Medical Association, Volume 130, pages 199-204 by Shlam
and Noorlander. A bougie 5 centimeters long and 0.5 centimeter in
diameter of this example was found to provide effective medication
for four to six weeks, almost the extent of the entire dry
period.
In general, the literature has numerous references to show that
glycolic/lactic copolyesters and their hydrolysis products are
nontoxic and harmless when exposed to human or animal tissues.
EXAMPLE II
Pure crystalline glycolic acid, 217 grams, USP lactic acid (85%),
105 milliliters, and 394 milliliters of distilled water were
introduced into the resin kettle as in Example 1, and water was
distilled off under atmospheric pressure until the pot temperature
reached about 180.degree. C and the distillation was then continued
under aspirator vacuum until the pot temperature reached
205.degree. C, a total distillation time of about 10 hours. The
acid number of the cooled solid melt was 0.819 milliequivalents
carboxyl per gram of product, indicating a molecular weight of
1200.
One part by weight of this polyester containing 70 mole % glycolic
acid, with a molecular weight of 1200, and one part by weight of
oxytetracycline hydrochloride are intimately mixed in a Bradender
Mixer. The admixture is then injected into molds to provide
elongated dosage forms with tapered ends as bougees.
EXAMPLE III
Glycolic acid in aqueous solution, 570 milliliters containing 465
grams of acid, USP lactic acid (85%), 140 milliliters, and 470
milliliters of distilled water were introduced into the resin
kettle as in Example 1, and water was distilled off under
atmospheric pressure until the pot temperature reached about
180.degree. C and the distillation was then continued under
aspirator conditions until the pot temperature reached 255.degree.
C, a total distillation time of about 16 hours. The acid number of
the cooled solid melt was 0.670 milliequivalents carboxyl per gram
of product, indicating a molecular weight of 1500.
Two parts by weight of this polyester containing 79 mole % glycolic
acic, with a molecular weight of 1500, and one part by weight of
tetracycline hydrochloride are intimately mixed in a Brabender
Mixer. The mixture is then injected into molds to provide elongated
dosage forms with tapered ends as bougies.
EXAMPLE IV
Glycollic acid in aqueous solution, 314 milliliters containing 794
milligrams per milliliter by titration, USP lactic acid (85%), 190
milliliters, and 300 milliliters of distilled water were introduced
into the resin kettle as in Example 1 and water was distilled off
under atmospheric pressure until the pot temperature reached about
180.degree. C and the distillation was then continued under
aspirator conditions until the pot temperature reached 201.degree.
C, a total of about 16 hours. The acid number of the cooled solid
melt was 0.81 milliequivalents carboxyl per gram of product,
indicating a molecular weight of 1200.
One part by weight of this lactic acid modified polyglycolide
containing 63 mole % of glycolic acid and one part by weight of an
admixture of neomycin and polymixin B containing 80 weight percent
neomycin is admixed and formed into bougies as described in the
previous examples.
EXAMPLE V
In this example, a portion of the polyester-chlortetracycline mix
of Example I was ground and the resulting small particles or beads
were suspended in peanut oil to provide a suspension containing
about 50% by weight of solids. The suspension was found to be
self-sterilizing. It can be packaged in disposable syringes and
when infused into cow's udders, was found to be effective
medicinally with no indication of udder irritation.
As the glycolic acid content increases, the resulting polyesters
become harder, their softening point increases, and they show less
tendency toward caking, all of these being desirable changes.
Polyesters with a glycolic acid content between about 60 and 80
mole % are transparent brittle solids melting at or below
60.degree. C.
In addition to the polyester and antimicrobial agent, other
pharmaceutic aids can be incorporated into the dosage forms of this
invention in relatively minor amount, i.e. up to about 5% by weight
of the dosage form. These pharmaceutic aids include cobalt
chloride, certain steroids, enzymes, chlorbutanol,
polyvinylpyrrolidone, benzyl alcohol, amorphous silicas, sodium
chloride, fatty acids and emulsifiers.
In addition to the peanut oil of Example V, other vegetable oils
such as castor oil, cottonseed oil, sunflower seed oil, rapeseed
oil and corn oil can be employed. Also, glycols such as the
polyethylene and polypropylene glycols are suitable. The oil
suspensions can contain from about 30 to 50 weight percent of the
solid dosage forms of this invention. The suspensions can be
packaged in disposable syringes or can by administered by an
infusion cannula.
* * * * *